SUV39H1-dependent methyl-degron is a critical regulator of skeletal homeostasis

Qian Li; Hongguang An; Rushui Bai; Qiannan Sun; Ruili Yang; Tianyi Xin; Zimeng Zhuang; Yuntao Lu; Yunyi Tang; Gengyao Chen; Weifang Zhang; Yu Zhang; Bing Han

doi:10.1016/j.celrep.2025.115910

SUV39H1-dependent methyl-degron is a critical regulator of skeletal homeostasis

Cell Rep. 2025 Jun 27;44(7):115910. doi: 10.1016/j.celrep.2025.115910. Online ahead of print.

Authors

Qian Li¹, Hongguang An², Rushui Bai³, Qiannan Sun³, Ruili Yang³, Tianyi Xin³, Zimeng Zhuang³, Yuntao Lu³, Yunyi Tang², Gengyao Chen², Weifang Zhang², Yu Zhang⁴, Bing Han⁵

Affiliations

¹ Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China. Electronic address: qianli@bjmu.edu.cn.
² Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
³ Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China.
⁴ Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China. Electronic address: zhang_yu@hsc.pku.edu.cn.
⁵ Department of Orthodontics, Peking University School and Hospital of Stomatology, National Engineering Laboratory for Digital and Material Technology of Stomatology, Beijing Key Laboratory of Digital Stomatology, Beijing 100081, China. Electronic address: kqbinghan@bjmu.edu.cn.

PMID: 40581930
DOI: 10.1016/j.celrep.2025.115910

Abstract

Bone homeostasis and skeletal fragility are sexually dimorphic in humans, with postmenopausal women at the highest risk of osteoporosis. Here, we identify X-linked methyltransferase SUV39H1 as a suppressor of osteogenesis in females. Both experiments in primary samples and Suv39h1-deficient mice show enhanced osteogenesis upon SUV39H1 ablation with gender differences. Transcriptomic analysis reveals the aberrant NF-κB activation and inflammation signatures independent of H3K9me3 underlying SUV39H1-inhibited osteogenesis. Surprisingly, SUV39H1 shows a unique cytoplasmic distribution in female osteoblasts and is directly engaged in inflammation response by catalyzing IκBα methylation at lysine 38 adjacent to its degradation motif. This SUV39H1-deposited methylation mark signals UACA binding and subsequently restrains bone formation by provoking IκBα destabilization. Importantly, intrinsically improved osteogenesis by Suv39h1 depletion ameliorates ovariectomy-induced osteoporotic bone loss. Together with the chronologically elevated female SUV39H1 levels, these data identify an SUV39H1-governed molecular amplifier in sexually divergent skeletal remodeling and highlight its potential as therapeutic avenue for osteoporosis.

Keywords: CP: Developmental biology; CP: Molecular biology; IκBα; NF-κB; SUV39H1; bone homeostasis; degradation; inflammation; methylation; osteogenic differentiation; protein stability; sexual dimorphism.